Chymase is one of neutral serine proteases (about 30 kD), and since it is an enzyme which converts angiotensin I into angiotensin II in tissues [J. Biol. Chem., vol.265, pp.22348 (1990)], it is said to be associated with induction of cardiac or circulatory diseases caused by angiotensin II. In addition, since chymase has been revealed to have the activity of promoting activation from collagenase to active collagenase, limitative degradation of extracellular matrix, thrombin or IgG, and release of histamine from mast cells, it is thought that chymase is also involved in allergic or inflammatory diseases. Further, although the action of chymase in the ocular tissue has not been completely elucidated, it is thought to be involved in regulating ophthalmic circulation (ophthalmic blood stream, aqueous humor circulation) and ciliary muscle. From the aforementioned wide activities of chymase in a living body, it is expected that an agent which inhibits such the enzyme is useful as an agent for preventing and treating various diseases.
As a chymase inhibiting agent, there have been previously known an imidazolidine derivative [(WO 96/04248 (counterparts: EP721944, U.S. Pat. No. 5,691,335)], an acetamide derivative [WO 98/09949 (counterpart: EP936216)], a triazinesulfone derivative (JP-H10-245384 A), a thiazolidine derivative (JP-2000-95770 A, JP-2000-103785 A), a quinazoline derivative (WO 97/11941), a phenolester derivative (JP-H10-87567A), a thiazine derivative (EP 0713876), a heterocyclic amide compound [WO 96/33974 (counterpart: EP826671, U.S. Pat. No. 5,948,785), WO 98/18794 (counterpart: EP940400, U.S. Pat. No. 6,080,738)], a peptide compound [Proc. Natl. Acad. Sci. U.S.A., vol.92, pp6738 (1995)], a hydantoin derivative (JP-H09-31061A), and so on. However, these compounds have not been put into practice yet.
Tryptase, like chymase, belongs to a serine protease family, and is isolated and purified from human lung as a protease having the trypsin-like substrate specificity [J. Biol. Chem, vol. 259, pp11046, (1984)]. Tryptase is present mainly in mast cells, and is also present in lymphocyte and bronchial mucous secreting cells, and is characterized in that, even after released to outside cells, the activity is sufficiently maintained in plasma or extracellular space. In mast cells, a majority of tryptase is stored in secretory granules and, when cells are activated, tryptase together with other enzymes (peroxidase, chymase etc.) and chemical mediators (e.g. histamine. leukotrienes, prostaglandins) is released by degranulation [N. Engl. J. Med., vol. 316, pp1622 (1987)].
Tryptase is related to a variety of diseases. For example, since tryptase increases the contractility of airway smooth muscle by inactivating a vasoactive intestinal peptide having the broncodilatory activity, it is said to be one cause for asthma [J. Pharmacol. Exp. Ther., vol. 244, pp133 (1988)]. In addition, tryptase has been shown to promote cell proliferation of fibroblast, and is said to be involved in interstitial pneumonia, pulmonary fibrosis, hepatic fibrosis, hepatic cirrhosis and pterygium [J. Clin. Invest., vol. 88, pp493 (1991), J Jpn Ophthalmol Soc, vol. 101, pp662 (1997)]. In addition, since tryptase activates prostoromelisin to cause activation of collagenase, and initiate destruction of cartilage and periodontal connecting tissue, tryptase may be a cause for arthritis or periodontal disease, and may be involved in other various tissue inflammations and re-building. Further, since tryptase cleaves a calcitonin gene-related peptides, it is involved in neurogenic inflammation [Am. J. Respir. Cell Mol. Biol., vol. 4, pp387 (1991)]. Tryptase promotes blood coagulation disorder by inactivating the coagulation precursor function of high-molecular kininogen, and degrading fibrinogen. Viruses having an outer membrane glycoprotein such as influenza and Sendai viruses are fused with a target cell membrane by degradation of the glycoprotein by tryptase and invade the cells. Examples of the virus include parainfluenza viruses, RS viruses, measles viruses and mumps viruses. As a tryptase inhibiting agent, natural leupeptin and antipain and some benzamidine derivatives are known [Biol. Chem. Hoppe-Seyler, vol.369, pp617 (1988)]. Besides, there are known an aminohexanoyl derivative (JP 2000-302675A), a polyfluoroalkylated tripeptide derivative [JP-H05-112598 A (counterparts: EP503203, U.S. Pat. Nos. 5,391,705, 5,498,779, 5,563,156)], a peptide derivative [JP-H08-507768 A (counterpart: EP688337)], a secretory leukocyte protease inhibitor (JP-10-505833 A), a leech-derived polypeptide [JP-H09-500532 A (counterparts: EP714408, U.S. Pat. No. 5,972,698)], a guanidine derivative (JP-Re 97/037969 A), antileukoprotease (JP-Re 95/025539 A), associated peptides (JP Re97/003694-A), and so on. However, these compounds have not been put into practice yet.